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Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions.

ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis. We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions. We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination. Zinc in MS lesions was generally decreased, paralleling myelin loss. Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques. Upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.

SUBMITTER: Popescu BF

PROVIDER: S-EPMC5486634 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions.

Popescu Bogdan F BF Frischer Josa M JM Webb Samuel M SM Tham Mylyne M Adiele Reginald C RC Robinson Christopher A CA Fitz-Gibbon Patrick D PD Weigand Stephen D SD Metz Imke I Nehzati Susan S George Graham N GN Pickering Ingrid J IJ Brück Wolfgang W Hametner Simon S Lassmann Hans H Parisi Joseph E JE Yong Guo G Lucchinetti Claudia F CF

Acta neuropathologica 20170322 1

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quan ...[more]

PMID: 28332093

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Project description:Background and purposeSlowly expanding/evolving lesions measured by conventional T1-weighted/T2-weighted brain MR imaging may contribute to progressive disability accumulation in MS. We evaluated the longitudinal change in myelin and axonal tissue integrity in white matter slowly expanding/evolving lesions by means of the magnetization transfer ratio and DTI radial diffusivity.Materials and methodsSlowly expanding/evolving lesions were detected within the Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Participants With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex (SYNERGY) Phase 2 clinical trial dataset (NCT01864148), comprising patients with relapsing-remitting and secondary-progressive MS (n = 299) with T1-weighted/T2-weighted MR imaging at all trial time points (baseline to week 72).ResultsCompared with non-slowly expanding/evolving lesions (areas not classified as slowly expanding/evolving lesion) of baseline nonenhancing T2 lesions, slowly expanding/evolving lesions had a lower normalized magnetization transfer ratio and greater DTI radial diffusivity, both in patients with relapsing-remitting MS (n = 242) and secondary-progressive MS (n = 57, P < .001 for all). Although the changes with time in both the normalized magnetization transfer ratio and DTI radial diffusivity between slowly expanding/evolving lesions and non-slowly expanding/evolving lesions were positively correlated (P < .001), a decrease in the normalized magnetization transfer ratio and a greater increase in DTI radial diffusivity were observed in slowly expanding/evolving lesions versus non-slowly expanding/evolving lesions from baseline to week 72 in relapsing-remitting MS and secondary-progressive MS (P < .001 for all).ConclusionsPatterns of longitudinal change in the normalized magnetization transfer ratio and DTI radial diffusivity in slowly expanding/evolving lesions were consistent with progressive demyelination and tissue loss, as seen in smoldering white matter MS plaques.

Project description:BACKGROUND AND PURPOSE:A hyperintense rim on susceptibility in chronic MS lesions is consistent with iron deposition, and the purpose of this study was to quantify iron-related myelin damage within these lesions as compared with those without rim. MATERIALS AND METHODS:Forty-six patients had 2 longitudinal quantitative susceptibility mapping with automatic zero reference scans with a mean interval of 28.9 ± 11.4 months. Myelin water fraction mapping by using fast acquisition with spiral trajectory and T2 prep was obtained at the second time point to measure myelin damage. Mixed-effects models were used to assess lesion quantitative susceptibility mapping and myelin water fraction values. RESULTS:Quantitative susceptibility mapping scans were on average 6.8 parts per billion higher in 116 rim-positive lesions compared with 441 rim-negative lesions (P < .001). All rim-positive lesions retained a hyperintense rim over time, with increasing quantitative susceptibility mapping values of both the rim and core regions (P < .001). Quantitative susceptibility mapping scans and myelin water fraction in rim-positive lesions decreased from rim to core, which is consistent with rim iron deposition. Whole lesion myelin water fractions for rim-positive and rim-negative lesions were 0.055 ± 0.07 and 0.066 ± 0.04, respectively. In the mixed-effects model, rim-positive lesions had on average 0.01 lower myelin water fraction compared with rim-negative lesions (P < .001). The volume of the rim at the initial quantitative susceptibility mapping scan was negatively associated with follow-up myelin water fraction (P < .01). CONCLUSIONS:Quantitative susceptibility mapping rim-positive lesions maintained a hyperintense rim, increased in susceptibility, and had more myelin damage compared with rim-negative lesions. Our results are consistent with the identification of chronic active MS lesions and may provide a target for therapeutic interventions to reduce myelin damage.

Project description:Ferroptosis is a form of lipid peroxidation-mediated cell death and damage triggered by excess iron and insufficiency in the glutathione antioxidant pathway. Oxidative stress is thought to play a crucial role in progressive forms of multiple sclerosis (MS) in which iron deposition occurs. In this study we assessed if ferroptosis plays a role in a chronic form of experimental autoimmune encephalomyelitis (CH-EAE), a mouse model used to study MS. Changes were detected in the mRNA levels of several ferroptosis genes in CH-EAE but not in relapsing-remitting EAE. At the protein level, expression of iron importers is increased in the earlier stages of CH-EAE (onset and peak). While expression of hemoxygenase-1, which mobilizes iron from heme, likely from phagocytosed material, is increased in macrophages at the peak and progressive stages. Excess iron in cells is stored safely in ferritin, which increases with disease progression. Harmful, redox active iron is released from ferritin when shuttled to autophagosomes by 'nuclear receptor coactivator 4' (NCOA4). NCOA4 expression increases at the peak and progressive stages of CH-EAE and accompanied by increase in redox active ferrous iron. These changes occur in parallel with reduction in the antioxidant pathway (system xCT, glutathione peroxidase 4 and glutathione), and accompanied by increased lipid peroxidation. Mice treated with a ferroptosis inhibitor for 2 weeks starting at the peak of CH-EAE paralysis, show significant improvements in function and pathology. Autopsy samples of tissue sections of secondary progressive MS (SPMS) showed NCOA4 expression in macrophages and oligodendrocytes along the rim of mixed active/inactive lesions, where ferritin+ and iron containing cells are located. Cells expressing NCOA4 express less ferritin, suggesting ferritin degradation and release of redox active iron, as indicated by increased lipid peroxidation. These data suggest that ferroptosis is likely to contribute to pathogenesis in CH-EAE and SPMS.

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Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions.

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Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions.

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